The long-term goal of the proposed work is to increase our understanding of how brain function is impaired by diabetes and insulin resistance. The immediate objectives of the proposed work are to carefully characterize the in vivo brain in type 2 diabetes and insulin resistance syndrome (relative to age-, education-, and gender-matched nominally normal individuals with normal glucose tolerance) and to ascertain whether observed reductions in declarative memory performance among diabetics and individuals with insulin resistance are associated with specific hippocampal volume reductions. All evaluations will use standardized and reliable methods. We hypothesize that deficits will be related to the degree of insulin resistance, i.e., type 2 diabetics > non-diabetic insulin resistant > control. Because significant vascular disease can have an impact on cognitive performance, we will study individuals who do not have extensive vascular pathology, and we will monitor subtle levels of micro-vessel disease so as to be in a position to account for those effects statistically in secondary analyses. Given the extensive associations between hippocampal integrity and cortisol levels and regulation, as well as the known relationships between regulation of peripheral glucose and cortisol secretion, in secondary analyses we will account for the potential effects of cortisol on the hypothesized relationships. We propose to study three groups of age, gender, and education matched individuals, who do not have evidence of significant large vessel atherosclerosis, 45-60 years of age, with at least a high school education, and 50% female, as follows: 50 normal individuals with normal glucose tolerance, 50 individuals with fasting glucose levels in the non-diabetic range and with insulin resistance, and 50 patients with type-2 diabetes, who have never been treated with insulin or insulin secretagogues and who are well controlled on diet and/or oral agents. The improved understanding to be provided by this study may suggest that the brain be formally evaluated as a site of potential complications in diabetes. In addition, the proposed study may add to the rationale to use behavioral and pharmacological interventions aimed at improving insulin sensitivity to improve memory problems among mid-life individuals. Lastly, this study may also contribute to a more general understanding of hippocampal atrophy in conditions other than diabetes where there may be HPA axis dysregulation. [unreadable] [unreadable]